Cyclosporines form a class of polypeptides commonly possessing immunosuppressive and anti-inflammatory activity. The most commonly known cyclosporine is cyclosporine-A. It is commercially available as Sandimmune.RTM. in a soft gelatin capsule dosage form. Other forms of cyclosporines include cyclosporine-B, -C, -D, and their derivatives. It should be understood that in this specification the terms "cyclosporine" or "cyclosporines" refer to any of the several cyclosporines or to any mixture of the several cyclosporines.
Cyclosporine is a hydrophobic material exhibiting poor bioavailability. The liquid oral formulations containing oils, ethanol and a trans-esterification product of a triglyceride and a polyol as a surfactant (U.S. Pat. No. 4,388,307) have a variety of difficulties, such as unpleasant taste, which is unacceptable for long-term therapy. The use of the soft gelatin capsule dosage to mask the taste of the solution entails specialized packaging of the encapsulated product in an air tight blister or aluminum foil blister package. This renders the product more bulky and more expensive. The storage conditions are far from ideal.
The bioavailability of these liquid formulations or the soft gelatin capsule formulation containing ethanol, oils and Labrafil surfactant, is low and variable, and reported to be about 30%.
Recently, U.S. Pat. No. 5,342,625 was issued claiming an improved formulation of cyclosporine in the form of a microemulsion pre-concentrate. In addition to the cyclosporine, this formulation requires a hydrophilic phase, a lipophilic phase, and a surfactant. The microemulsion pre-concentrate is claimed to provide enhanced bioavailability. The hydrophilic phase of the microemulsion concentrate comprises either 1,2-propylene glycol or: EQU R.sub.1 --O--(CH.sub.2)!.sub.x --OR.sub.2
where R.sub.1, R.sub.2 =C.sub.1-5 alkyl or tetrahydrofurfuryl, and x=1 to 6. R.sub.2 may also be hydrogen. Such ethers are commercially available under the trade name of Transcutol, Colycofurol and Glycofurol. The hydrophilic phase may additionally contain C.sub.1-5 alkanols such as ethanol. The hydrophilic component of U.S. Pat. No. 5,342,625, an essential component for microemulsion preconcentrate, provides cosolvency for the cyclosporine.
The formulations of both U.S. Pat. Nos. 4,388,307 and 5,342,625 include the use of hydrophilic components, such as ethanol or 1,2-propylene glycol, which require specialized packaging, such as aluminum foil blister. U.S. Pat. No. 5,342,625 further requires the use of other ethers, such as Transcutol and Glycofurol, which are restricted by several regulatory agencies worldwide including the FDA because they are not considered "Generally Recognized As Safe" (GRAS) for oral use. Therefore, there is a need for an improved formulation that can be inexpensively and conventionally packaged, such as in glass or OHD polyethylene bottles. It is also desirable that the components of the formulation consist only of "GRAS" excipients for oral use.
The formulation of U.S. Pat. No. 5,154,930 requires a non-aqueous water-miscible solvent for the medication, preferably ethanol or a polyethylene glycol. The patent is different from the present invention not only in requiring the hydrophilic phase, but also in requiring a desalted charged lipid.
Alcohol-free emulsion pre-concentrates are known, but have drawbacks. For example, the formulation of U.S. Pat. No. 5,206,219 requires a multitude of ingredients, including the medication, a protease inhibitor, cholesterol, a phospholipid, a surfactant, a polyol and a lipid solvent. It is desirable to minimize the number of ingredients in order to reduce the chance of, for example, adverse reactions in the person taking the medication.
Kurihara, et al., U.S. Pat. No. 4,990,337, discloses improved solubility of cyclosporines in medium chain mono- and di-glycerides. All of the examples with cyclosporine and a surfactant involve making two solutions, one containing cyclosporine and a glyceride, and the other containing water and a surfactant. The two solutions are mixed and then emulsified with laboratory equipment.
We have discovered that if cyclosporine is dissolved in a polar lipid and mixed with a surfactant, then the mixture unexpectedly completely and reliably self-emulsifies upon contact with an aqueous phase such as water.